Pressure-sensitive adhesive tapes have been used for more than half a century for a variety of marking, holding, protecting, sealing, and masking purposes. The earliest medical applications where the product was referred to as an adhesive plaster were not pressure-sensitive adhesives. These were, in fact, crude mixtures of natural rubber plasticized and tackified with wood rosin derivatives and turpentine and heavily pigmented with zinc oxide. These tape-like products served their purpose, but with the advent of truly pressure-sensitive adhesives, they were replaced.
The term "pressure-sensitive adhesive" (PSA) has a precise technical definition and has been dealt with extensively in the technical literature, examples of which are Chapter 17 of Houwink and Salomon "Adhesion and Adhesives", Volume 2, Elsivier Publishing Company, 1967, and the "Handbook of Pressure-Sensitive Technology", Second Edition, Edited by Donatas Satas, Van Nostrand Reinhold Company, 1989.
Fundamentally, PSAs require a delicate balance of viscous and elastic properties which result in a 4-fold balance of adhesion, cohesion, stretchiness, and elasticity. In essence, PSA products have sufficient cohesiveness and elasticity so that, despite their aggressive tackiness, they can be handled with the fingers and removed from smooth surfaces without leaving residue.
The difficulty of adhering tape or other devices to the human skin has long been recognized. The irregular and complex surface of the skin presents difficulties in itself and the wide variation in the skin surface from individual to individual and from location to location on the same individual multiply these difficulties.
Adhesives used in applications that contact the skin require clinical testing that supports a claim that the adhesive is hypoallergenic. These clinical studies are used to confirm that the PSA is neither irritating nor sensitizing to skin.
Acrylic PSAs have been used for many years in medical and surgical applications to adhere items to the skin. U.S. Pat. No. 3,121,021 (Copeland) used an acrylic copolymer of the type described in U.S. Pat. No. 2,884,126/RE24,906 (Ulrich) to provide a porous, surgical adhesive tape with very acceptable skin adhesion performance. A disadvantage encountered using some acrylic PSAs was adhesion build, also known as compliance failure, when the acrylic PSA was in contact with the skin for long periods of time.
In U.S. Pat. No. 3,475,363 (Gander), the compliance failure in acrylate PSAs was overcome by employing a crosslinking agent, dimethylaminoethyl methacrylate, to ensure adhesion to the skin without deleterious effects. Other crosslinking agents have been described for the same purpose: U.S. Pat. Nos. 4,693,776 (Krampe et al.) and 4,732,808 (Krampe et al.) both describe a skin adhesive of an acrylic polymer having grafted to the backbone, polymeric moieties having a glass transition temperature greater than about 20.degree. C. and a weight average molecular weight above about 2000, in order to provide an adhesive composition with a creep compliance value of greater than 1.2.times.10.sup.-5 cm.sup.2 /dyne. U.S. Pat. No. 3,532,652 (Zang) describes the partial crosslinking of an acrylate polymer with polyisocyanate to overcome weakening of the cohesive strength of the polymer by migration of skin oils and the like into the adhesive.
Compliance failure can also be remedied by crosslinking an acrylate PSA with a mono-ethylenically unsaturated aromatic ketone monomer using ultra-violet radiation, as described in U.S. Pat. No. 4,737,559 (Kellen et al.). While such ultra-violet irradiation of a crosslinking agent with an acrylate PSA in the presence of a photoinitiator may be useful for some medical applications, it is not useful for medical devices which have a component, e.g. a drug, with the potential of interaction with any residual unreacted photoinitiator, crosslinking agent, or detrimental byproducts of the ultra-violet radiation exposure.
One type of medical device having components which may be susceptible to deleterious interaction is a transdermal delivery device having among other components, a pressure-sensitive adhesive layer and an active agent to be released under controlled conditions to and through the surface of the skin. In U.S. Pat. No. 4,714,655 (Bordoloi et al.), a heat-sensitive material, such as medicaments, fragrances, or repellants, is mixed with a fluid pre-polymer and subjected to ultra-violet radiation, electron beam radiation, or a combination thereof to achieve chain extension and/or crosslinking polymerization, in order to achieve a pressure-sensitive adhesive having the heat-sensitive material entrained therein to yield a transdermal delivery system known as drug-in-adhesive.
Other types of transdermal delivery devices provide multiple-layered constructions where the pressure-sensitive adhesive layer is between the skin and the active agent, typically a pharmaceutical potentially susceptible to processing conditions and potentially reactive with other compounds. Thus, the components in the transdermal delivery device must be inert to the active agent and must be free of unreacted raw materials, by-products and the like which are common to both chemical crosslinking and ultra-violet photoinitiated crosslinking of acrylic PSA's.
Further, the number of active agents suitable for transdermal delivery devices is restricted by the inability of molecules with either (a) a molecular weight too high, or (b) a solubility profile not compatible with the skin structure, to permeate the skin at an acceptable rate for optimal therapeutic blood levels. Therefore, the active agent is often formulated with an excipient, such as a penetration enhancing agent, at a concentration that enables the drug to permeate the skin at the targeted permeation rate and achieve therapeutic blood levels.
Incorporation of penetration enhancing agents in a transdermal device has led to failure of the physical integrity of the construction of the device. Penetration enhancing agents are used in conjunction with the drug to enable the drug to flow through the skin. The transdermal delivery device is often constructed in such a manner that the penetration enhancing agent comes into contact with the pressure sensitive adhesive. The physical properties of the pressure sensitive adhesive can change due to the possible plasticization of the pressure sensitive adhesive by the penetration enhancing agent. The alteration of physical properties can result in delamination of the transdermal delivery device construction, cohesive failure of the pressure sensitive adhesive, and other losses of the ideal physical properties required for a skin adhesive during the course of its storage and usage.
In addition to penetration enhancing agents, other excipients, including alcohol-based drug excipients, are often used with a pharmaceutical for formulation processing, dilution, or other handling reasons. These excipients also can come into contact with the pressure sensitive adhesive with similar potential for alteration of physical properties and similar potential for causing deleterious results for the transdermal device.
Specifically formulated or processed pressure-sensitive adhesives used for a variety of purposes not involving active agents like pharmaceuticals have been known to be resistant to solvents. U.S. Pat. No. 2,973,286 (Ulrich) employed benzoyl peroxide or other organic peroxides to resist the effects of solvents affecting the manufacture of PSA industrial tapes. U.S. Pat. No. 2,925,174 (Stow) provided improved solvent resistance by reaction with liquid epoxy resins and with 2-ethylhexane diol-1,3 for pressure-sensitive adhesive tapes. U.S. Pat. No. 2,956,904 (Hendricks) describes approximately doubling the cohesive strength of pressure-sensitive adhesive used for electrical tapes by high-energy electron beam irradiation such that the crosslinked elastomers were no longer dispersible in the solvents used in coating the adhesive layer on the carrier web or in other common solvents.
Electron beam curing of other pressure-sensitive adhesives to provide solvent resistance has also been described in U.S. Pat. No. 4,695,604 (Amirsakis) for polyurethane resins; in U.S. Pat. No. 4,432,848 (Korpman) for an A-B-A block copolymer, where A represents a poly(monoalkenylarene) block and where B represents a polyisoprene block; in "Formulating to Enhance the Radiation Crosslinking of Thermal Plastic Rubber for Hot Melt Pressure-Sensitive Adhesives", (Ewins, Jr. and Erickson, Tappi Journal, June, 1988, pages 155-158), describing styrene-isoprene-styrene polymers crosslinked with electron beam radiation; and in PCT Patent Publication WO 89/00106 (Plamthottam et al.) for double-coated acrylic and rubber based pressure sensitive adhesive foam-like tapes.
Further, U.S. Pat. Nos. 4,699,146 and 4,750,482 describe a hydrophilic pressure-sensitive adhesive produced by ionizing radiation.
What is lacking in the art is a transdermal delivery device pressure-sensitive adhesive which is tolerant of excipients, such as penetration enhancing agents used in conjunction with the active agent being delivered at a rate through the device to the skin that achieves a therapeutic level.
While certain advances have been made in the minimizing compliance failure for skin PSA's, none have succeeded without employing chemical crosslinking agents alone or in combination with ultra-violet radiation initiated polymerization.
While other pressure-sensitive adhesives have been rendered solvent resistant through electron beam radiation, none of those pressure-sensitive adhesives have been used or contemplated for use in a device, having an active agent and its excipients, where that device is to be maintained in adhesive contact with human skin.
While transdermal delivery systems have been described which use electron beam radiation for polymerization of a liquid pre-polymer into a pressure-sensitive adhesive, the transdermal delivery system described therein does not employ the penetration enhancing agents now often used or desired to be used in transdermal delivery devices.
Thus, what is needed in the art of transdermal delivery devices is a hypoallergenic pressure-sensitive adhesive which is unreactive with the active agent to be delivered to the skin and which is tolerant of penetration enhancing agents and other excipients used with the active agent, such that there is no effective compliance failure of the pressure-sensitive adhesive during storage and usage.